MAC inhibitors suppress mitochondrial apoptosis

Pablo M. Peixoto; Shin Young Ryu; Agnes Bombrun; Bruno Antonsson; Kathleen W. Kinnally

doi:10.1042/BJ20090664

MAC inhibitors suppress mitochondrial apoptosis

Pablo M. Peixoto, Shin Young Ryu, Agnes Bombrun, Bruno Antonsson, Kathleen W. Kinnally

Research output: Contribution to journal › Article › peer-review

Abstract

MAC (mitochondrial apoptosis-induced channel) forms in the mitochondrial outer membrane and unleashes cytochrome c to orchestrate the execution of the cell. MAC opening is the commitment step of intrinsic apoptosis. Hence closure of MAC may prevent apoptosis. Compounds that blocked the release of fluorescein from liposomes by recombinant Bax were tested for their ability to directly close MAC and suppress apoptosis in FL5.12 cells. Low doses of these compounds (IC₅₀ values ranged from 19 to 966 nM) irreversibly closed MAC. These compounds also blocked cytochrome c release and halted the onset of apoptotic markers normally induced by IL-3 (interleukin-3) deprivation or staurosporine. Our results reveal the tight link among MAC activity, cytochrome c release and apoptotic death, and indicate thismitochondrial channel is a promising therapeutic target.

Original language	English (US)
Pages (from-to)	381-387
Number of pages	7
Journal	Biochemical Journal
Volume	423
Issue number	3
DOIs	https://doi.org/10.1042/BJ20090664
State	Published - Nov 1 2009

Keywords

Apoptosis
Cytochrome c release
Interleukin-3
Mitochondrial apoptosis-induced channel (MAC)
Patch-clamp
Staurosporine

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

Access to Document

10.1042/BJ20090664

Cite this

@article{08e9d4f8910a483e9f2d116f9f85ed7e,

title = "MAC inhibitors suppress mitochondrial apoptosis",

abstract = "MAC (mitochondrial apoptosis-induced channel) forms in the mitochondrial outer membrane and unleashes cytochrome c to orchestrate the execution of the cell. MAC opening is the commitment step of intrinsic apoptosis. Hence closure of MAC may prevent apoptosis. Compounds that blocked the release of fluorescein from liposomes by recombinant Bax were tested for their ability to directly close MAC and suppress apoptosis in FL5.12 cells. Low doses of these compounds (IC50 values ranged from 19 to 966 nM) irreversibly closed MAC. These compounds also blocked cytochrome c release and halted the onset of apoptotic markers normally induced by IL-3 (interleukin-3) deprivation or staurosporine. Our results reveal the tight link among MAC activity, cytochrome c release and apoptotic death, and indicate thismitochondrial channel is a promising therapeutic target.",

keywords = "Apoptosis, Cytochrome c release, Interleukin-3, Mitochondrial apoptosis-induced channel (MAC), Patch-clamp, Staurosporine",

author = "Peixoto, {Pablo M.} and Ryu, {Shin Young} and Agnes Bombrun and Bruno Antonsson and Kinnally, {Kathleen W.}",

year = "2009",

month = nov,

day = "1",

doi = "10.1042/BJ20090664",

language = "English (US)",

volume = "423",

pages = "381--387",

journal = "Biochemical Journal",

issn = "0264-6021",

publisher = "Portland Press Ltd.",

number = "3",

}

TY - JOUR

T1 - MAC inhibitors suppress mitochondrial apoptosis

AU - Peixoto, Pablo M.

AU - Ryu, Shin Young

AU - Bombrun, Agnes

AU - Antonsson, Bruno

AU - Kinnally, Kathleen W.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - MAC (mitochondrial apoptosis-induced channel) forms in the mitochondrial outer membrane and unleashes cytochrome c to orchestrate the execution of the cell. MAC opening is the commitment step of intrinsic apoptosis. Hence closure of MAC may prevent apoptosis. Compounds that blocked the release of fluorescein from liposomes by recombinant Bax were tested for their ability to directly close MAC and suppress apoptosis in FL5.12 cells. Low doses of these compounds (IC50 values ranged from 19 to 966 nM) irreversibly closed MAC. These compounds also blocked cytochrome c release and halted the onset of apoptotic markers normally induced by IL-3 (interleukin-3) deprivation or staurosporine. Our results reveal the tight link among MAC activity, cytochrome c release and apoptotic death, and indicate thismitochondrial channel is a promising therapeutic target.

AB - MAC (mitochondrial apoptosis-induced channel) forms in the mitochondrial outer membrane and unleashes cytochrome c to orchestrate the execution of the cell. MAC opening is the commitment step of intrinsic apoptosis. Hence closure of MAC may prevent apoptosis. Compounds that blocked the release of fluorescein from liposomes by recombinant Bax were tested for their ability to directly close MAC and suppress apoptosis in FL5.12 cells. Low doses of these compounds (IC50 values ranged from 19 to 966 nM) irreversibly closed MAC. These compounds also blocked cytochrome c release and halted the onset of apoptotic markers normally induced by IL-3 (interleukin-3) deprivation or staurosporine. Our results reveal the tight link among MAC activity, cytochrome c release and apoptotic death, and indicate thismitochondrial channel is a promising therapeutic target.

KW - Apoptosis

KW - Cytochrome c release

KW - Interleukin-3

KW - Mitochondrial apoptosis-induced channel (MAC)

KW - Patch-clamp

KW - Staurosporine

UR - http://www.scopus.com/inward/record.url?scp=70350109543&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350109543&partnerID=8YFLogxK

U2 - 10.1042/BJ20090664

DO - 10.1042/BJ20090664

M3 - Article

C2 - 19691447

AN - SCOPUS:70350109543

SN - 0264-6021

VL - 423

SP - 381

EP - 387

JO - Biochemical Journal

JF - Biochemical Journal

IS - 3

ER -

MAC inhibitors suppress mitochondrial apoptosis

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this